Effects of dietary epidermal growth factor supplementation on liver antioxidant capacity of piglets with intrauterine growth retardation.

The present experiment was conducted to study the effects of dietary epidermal growth factor (EGF) supplementation on the liver antioxidant capacity of piglets with intrauterine growth retardation (IUGR). The present study consists of two experiments. In experiment 1, six normal-birth-weight (NBW) and six IUGR newborn piglets were slaughtered within 2 to 4 h after birth to compare the effects of IUGR on the liver antioxidant capacity of newborn piglets. The results showed that compared with NBW piglets, IUGR piglets had a lower birth weight and liver relative weight; IUGR piglets had a higher serum malondialdehyde (MDA) level, liver MDA level and hydrogen peroxide (H2O2) level, and had a lower liver total antioxidant capacity (T-AOC) level and glutathione peroxidase (GSH-Px) activity; IUGR trended to increase serum alanine aminotransferase activity, aspartate aminotransferase activity, and H2O2 level, and trended to decrease liver total superoxide dismutase activity. In experiment 2, six NBW piglets, and 12 IUGR piglets weaned at 21 d of age were randomly divided into the NC group (NBW piglets fed with basal diet); IC group (IUGR piglets fed with basal diet), and IE group (IUGR piglets fed with basal diet plus 2 mg/kg EGF), and feeding for 14 d. Organ index, serum parameters, liver antioxidant capacity, and liver antioxidant-related genes expression were measured. The results showed that compared to the IC group, dietary EGF supplementation (IE group) significantly reduced serum malondialdehyde level and H2O2 level, and liver protein carbonyl (PC) level and 8-hydroxydeoxyguanosine level of piglets with IUGR; dietary EGF supplementation (IE group) significantly increased serum T-AOC level, liver T-AOC level and GSH-Px activity; dietary supplemented with EGF (IE group) enhanced liver Nrf2, NQO1, HO1, and GPX1 mRNA expression compared to IC group. Pearson's correlation analysis further showed that EGF can alleviate liver oxidative injury caused by IUGR and improve the performance of IUGR piglets. In conclusion, EGF exhibited potent protective effects on IUGR-induced liver oxidative injury, by activating the Nrf2 signaling pathway to mediate the expression of downstream antioxidant enzymes and phase II detoxification enzymes (NQO1 and HO1), thereby alleviating liver oxidative damage and promoting the growth performance of IUGR piglets.

The liver is an important metabolic and secretory organ in vertebrates, which plays an important role in the overall health of animals. Studies have shown that intrauterine growth retardation (IUGR) can cause liver injury in piglets, which is unfavorable to the growth and development of piglets. Epidermal growth factor (EGF) has antioxidant properties, but its effect on liver oxidative damage caused by IUGR remains uncertain. In the present study, we chose newborn piglets with low birth weight as the IUGR models to investigate whether IUGR could cause oxidative damage in the liver. Then, the diet supplemented with EGF was fed to IUGR piglets to study the effects of EGF supplementation on the liver antioxidant function of IUGR-weaned piglets. Results showed that IUGR caused serious damage to the liver of piglets, while dietary EGF supplementation could reverse the oxidative injury induced by IUGR to some extent. Therefore, this study confirmed that EGF has positive effects on the liver health of piglets with IUGR.

Lipid profile after omega-3 supplementation in neonates with intrauterine growth retardation: a randomized controlled trial.

BACKGROUND: Neonates with intrauterine growth restriction (IUGR) have a high lipid profile that predisposes them to cardiovascular disease later in life. We aimed to evaluate the effect of omega 3 supplementation on serum leptin level, lipid profile, and growth in neonates with IUGR. METHODS: This clinical trial was conducted on 70 full-term neonates with IUGR. Neonates were randomly divided into two equal groups; the treatment group: received omega 3 supplement (40 mg/kg/day) for 2 weeks after the establishment of full feeding, and the control group, who were followed up to full feeding without any supplementation. Serum leptin level, total cholesterol (TC), high-density lipoprotein (HDL), triglycerides (TG), low-density lipoprotein (LDL), and anthropometric measurement were evaluated at admission and after 2 weeks of omega 3 supplementation in both groups. RESULTS: After treatment, HDL significantly increased, unlike TC, TG, LDL, LDL, and serum leptin levels, which significantly decreased in the treatment group compared to the control group after treatment. Interestingly, weight, length, and ponderal index greatly increased in omega 3-treated neonates compared to the control group. CONCLUSION: Omega 3 supplementations lowered serum leptin level, TG, TC, LDL, and VLDL but increased HDL and growth in neonates with IUGR. CLINICAL TRIAL REGISTRATION: The study was registered at clinicaltrials.gov (NCT05242107). IMPACT: Neonates with intrauterine growth retardation (IUGR) were reported to have a high lipid profile that predisposes them to cardiovascular disease later in life. Leptin is a hormone that adjusts dietary intake and body mass and has a significant role in fetal development. Omega 3 is known to be essential for neonatal growth and brain development. We aimed to evaluate the effect of omega 3 supplementation on serum leptin level, lipid profile, and growth in neonates with IUGR. We found that omega 3 supplementations lowered serum leptin level and serum lipid profile but increased high density lipoprotein and growth in neonates with IUGR.

Dietary ferulic acid supplementation improves antioxidant capacity and lipid metabolism in liver of piglets with intrauterine growth retardation.

Intrauterine growth retardation (IUGR) can result in early liver oxidative damage and abnormal lipid metabolism in neonatal piglets. Ferulic acid (FA), a phenolic compound widely found in plants, has many biological functions, such as anti-inflammation and anti-oxidation. Thus, we explored the effects of dietary FA supplementation on antioxidant capacity and lipid metabolism in newborn piglets with IUGR. In the study, 24 7-day-old piglets were divided into three groups: normal birth weight (NBW), IUGR, and IUGR + FA. The NBW and IUGR groups were fed formula milk as a basal diet, while the IUGR + FA group was fed a basal diet supplemented with 100 mg/kg FA. The trial lasted 21 days. The results showed that IUGR decreased absolute liver weight, increased transaminase activity, reduced antioxidant capacity, and disrupted lipid metabolism in piglets. Dietary FA supplementation enhanced absolute liver weight, reduced serum MDA level and ROS concentrations in serum and liver, markedly increased serum and liver GSH-PX and T-SOD activities, decreased serum HDL-C and LDL-C and liver NEFA, and increased TG content and HL activity in the liver. The mRNA expression related to the Nrf2-Keap1 signaling pathway and lipid metabolism in liver were affected by IUGR. Supplementing FA improved the antioxidant capacity of liver by down-regulating Keap1 and up-regulating the mRNA expression of SOD1 and CAT, and regulated lipid metabolism by increasing the mRNA expression level of Fasn, Pparα, LPL, and CD36. In conclusion, the study suggests that FA supplementation can improve antioxidant capacity and alleviate lipid metabolism disorders in IUGR piglets.

Association Between Enteral Supplementation With High-Dose Docosahexaenoic Acid and Risk of Bronchopulmonary Dysplasia in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: High-dose docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid, may affect the risk of bronchopulmonary dysplasia (BPD). However, high-level summative evidence supporting such clinical association in very preterm infants is lacking. Objective: To examine the association between enteral supplementation with high-dose DHA during the neonatal period and the risk of BPD in preterm infants born at less than 29 weeks' gestation. Data Sources: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, medRxiv, and ClinicalTrials.gov were searched from inception to August 1, 2022, for eligible articles with no language restrictions. Study Selection: Randomized clinical trials (RCTs) were eligible for inclusion (1) if their interventions involved direct administration of a minimum DHA supplementation of 40 mg/kg/d or breast milk or formula feeding of at least 0.4% of total fatty acids, and (2) if they reported data on either BPD, death, BPD severity, or a combined outcome of BPD and death. Data Extraction and Synthesis: Two investigators completed independent review of titles and abstracts, full text screening, data extraction, and quality assessment using the Cochrane Risk of Bias 2.0. Risk ratios (RRs) with 95% CIs were pooled using random-effect meta-analyses. Main Outcomes and Measures: Primary outcome was BPD using trial-specific definitions, which was further stratified for RCTs that used a more stringent BPD definition based on systematic pulse oximetry assessment at 36 weeks' postmenstrual age. Other outcomes were BPD, death, BPD severity, or combined BPD and death. Results: Among the 2760 studies screened, 4 RCTs were included, which involved 2304 infants (1223 boys [53.1%]; mean [SD] gestational age, 26.5 [1.6] weeks). Enteral supplementation with high-dose DHA was associated with neither BPD (4 studies [n = 2186 infants]; RR, 1.07 [95% CI, 0.86-1.34]; P = .53; I2 = 72%) nor BPD or death (4 studies [n = 2299 infants]; RR, 1.04 [95% CI, 0.91-1.18]; P = .59; I2 = 61%). However, an inverse association with BPD was found in RCTs that used a more stringent BPD definition (2 studies [n = 1686 infants]; RR, 1.20 [95% CI, 1.01-1.42]; P = .04; I2 = 48%). Additionally, DHA was inversely associated with moderate-to-severe BPD (3 studies [n = 1892 infants]; RR, 1.16 [95% CI, 1.04-1.29]; P = .008; I2 = 0%). Conclusions and Relevance: Results of this study showed that enteral supplementation with high-dose DHA in the neonatal period was not associated overall with BPD, but an inverse association was found in the included RCTs that used a more stringent BPD definition. These findings suggest that high-dose DHA supplementation should not be recommended to prevent BPD in very preterm infants.

Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction.

OBJECTIVE: The Accelerating Innovation for Mothers project established a new database of candidate medicines under development between 2000 and 2021 for five pregnancy-related conditions, including fetal growth restriction. The objective was to assess medicines for fetal growth restriction and their potential for clinical use globally. DESIGN: Landscape analysis. SETTING: Global (focus on low- and middle-income countries, LMICs). SAMPLE: Drugs, dietary supplements and biologics under investigation for prevention or treatment of fetal growth restriction. METHODS: A research pipeline database of medicines was created through searching AdisInsight, PubMed and various grant and clinical trial databases. Analysis of clinical and preclinical candidates were descriptive. MAIN OUTCOMES MEASURES: Fetal growth restriction candidates in clinical development were identified and ranked as high, medium or low potential based on prespecified criteria, including efficacy, safety and accessibility. RESULTS: Of the 444 unique candidates in the database across all five pregnancy-related conditions, 63 were for fetal growth restriction. Of these, 31 were in clinical development (phases I, II or III) and 32 were in preclinical development. Three candidates, aspirin, l-arginine and vitamin D, were ranked as having high potential as preventive agents. There were no high-potential candidates for treating fetal growth restriction, although five candidates were ranked as having medium potential: allylestrenol, dalteparin, omega-3 fatty acids, tadalafil, and United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP). CONCLUSIONS: l-Arginine, aspirin and vitamin D are promising, high-potential preventative agents for fetal growth restriction. Based on the medicines pipeline, new pharmacological agents for fetal growth restriction are unlikely to emerge in the near future.

Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction.

Intrauterine growth restriction (IUGR), one of the major complications of pregnancy, is characterized by low birth weight and results in higher risks for long-term problems including developing metabolic and cardiovascular diseases. Short-chain fatty acids (SCFAs), especially propionate, have been reported to correct glucose and lipid disorders in metabolic diseases. We hypothesized that maternal propionate supplementation could prevent glucose and lipid metabolic disturbance in hypoxia-induced IUGR. Here, in our study, maternal hypoxia was induced from gestational day (GD) 11 to GD 17.5 to establish an IUGR mouse model. Maternal propionate treatment reversed reduced birth weight in male IUGR offspring. Hepatic transcriptomics demonstrated that SP treatment significantly lowered glucose and lipid metabolism-related genes (Scd1, G6pc, Pck1 and Fasl) in IUGR offspring. KOG enrichment analysis showed that propionate-induced down-regulated differential expressed genes (DEGs) mainly belonged to lipid transport and metabolism. KEGG enrichment results showed that the down-regulated DEGs were mostly enriched in PPAR and FoxO signaling pathways. We also found that maternal oral administration of SP decreased serum lipid content, attenuated hepatic insulin resistance and liver lipid accumulation, reduced hepatic key gene expressions of gluconeogenesis and lipogenesis, increased energy expenditure and improved liver function in 11-week-old male IUGR offspring. These results indicate that maternal propionate supplementation increases birth weight and corrects hepatic glucose and lipid metabolic disturbance and energy expenditure in male mice born with IUGR, which may provide a basis for using propionate to treat IUGR disease.

l-arginine supplementation improved neonatal outcomes in pregnancies with hypertensive disorder or intrauterine growth restriction: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: Previous research established that the availability of l-arginine affects placental vascular development and fetal growth. However, practical details associated with the effects of l-arginine supplementation on the neonatal outcomes of hypertensive disorder (HD) and intrauterine growth restriction (IUGR) pregnancies are limited. METHODS: The PubMed, ScienceDirect, and Web of Science databases were searched for peer-reviewed literature published by September 30, 2021 to investigate the operational details of l-arginine supplementation in improving neonatal outcomes in complicated pregnancies. Standardized mean difference (SMD) and weighted mean difference (WMD) of continuous variables, as well as the risk ratio (RR) for categorical variables were pooled by random-effects models. RESULTS: The results indicated that l-arginine supplementation increased the plasma nitric oxide (NO) concentrations in IUGR pregnancies (SMD: 0.71; 95% CI: 0.45, 0.97; I2 = 0%), but decreased the risk of preeclampsia in HD mothers (RR: 0.49; 95% CI: 0.31, 0.76; I2 = 0%). Administration with l-arginine elevated birth weights both in hypertensive and IUGR pregnant women, with WMDs of 194.70 g (95% CI: 58.21, 331.20; I2 = 44.2%) and 134.00 g (95% CI: 43.53, 224.46; I2 = 42.4%), respectively. However, the intervention had no effect on gestational age except in HD pregnancies (WMD: 7.05 d; 95% CI: 3.16, 10.95; I2 = 36.5%). l-arginine administration during pregnancy significantly reduced the small for gestational age (SGA) risk of fetus both in HD (RR: 0.51; 95% CI: 0.31, 0.83; I2 = 0.0%) and IUGR mothers (RR: 0.46; 95% CI: 0.25, 0.88; I2 = 0.0%). Subgroup analyses revealed that l-arginine supplementation at <4 g/d dosage or for ≥1-month duration or in the third trimester had a greater effect on birth weights in HD women without proteinuria, but a higher l-arginine dosage was more beneficial for extending gestational age and reducing the risk of SGA in older pregnancies. Additionally, intravenous infusion of l-arginine, but not oral administration, significantly increased birth weight in IUGR pregnancies with elevated NO concentrations, although the recommended amount should be confined to <4 g/d. CONCLUSIONS: These findings provide practical guidelines for l-arginine supplementation to improve the birth outcomes of complicated pregnancies. REGISTRY NUMBER: CRD42021246290 (https://www.crd.york.ac.uk/PROSPERO).

Curcumin reduces oxidative stress and fat deposition in longissimus dorsi muscle of intrauterine growth-retarded finishing pigs.

Dietary curcumin possessing multiple biological activities may be an effective way to alleviate oxidative damage and fat deposition in intrauterine growth retardation (IUGR) finishing pigs. Therefore, this study was conducted to evaluate effects of dietary curcumin on meat quality, antioxidant capacity, and fat deposition of longissimus dorsi muscle in IUGR finishing pigs. Twelve normal birth weight (NBW) and 24 IUGR female piglets at 26 days of age were divided into 3 dietary groups: NBW (basal diet), IUGR (basal diet), and IUGR + Cur (basal diet supplemented with 200 mg/kg curcumin). The trial lasted for 169 days. Results showed that IUGR increased concentrations of malondialdehyde (MDA) and protein carbonyls (PC) and fat deposition in longissimus dorsi muscle. However, curcumin decreased the intramuscular fat content and the levels of MDA and PC and improved meat quality in IUGR pigs. Furthermore, curcumin inhibited the decrease of nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and decreased peroxisome pro liferator-activated receptors γ (PPARγ) expression in IUGR pigs. These findings suggested that dietary addition of 200 mg/kg curcumin could improve meat quality, alleviate oxidative stress through activating Nrf2 signaling pathway, and reduce fat deposition via inhibiting PPARγ expression in longissimus dorsi muscle of IUGR finishing pigs.

Effects of ferulic acid on the growth performance, antioxidant capacity, and intestinal development of piglets with intrauterine growth retardation.

Neonates with intrauterine growth retardation (IUGR) are prone to suffer from delayed postnatal growth and development during the early stages of life. Ferulic acid (FA) is a phenolic compound that is abundantly present in fruits and vegetables and has various health benefits. Hence, we explored whether FA supplementation could favorably affect the growth performance, antioxidant capacity, and intestinal development of piglets with IUGR. In total, eight normal-birth-weight (NBW) piglets and 16 piglets with IUGR (age, 7 d) were assigned to be fed either basic formula milk (NBW and IUGR groups, respectively) or basic formula milk supplemented with 100 mg/kg FA (IUGR + FA group) for 21 d. At necropsy, the serum and intestinal tissues were collected. FA supplementation increased (P < 0.05) the feed conversion ratio and serum total superoxide dismutase and catalase activities in piglets with IUGR. Moreover, FA supplementation elevated (P < 0.05) the duodenal lactase and maltase activities, jejunal villus height and jejunal maltase activity but reduced (P < 0.05) the duodenal crypt depth and duodenal and jejunal cell apoptosis, cleaved cysteinyl aspartic acid protease-3 (caspase-3) content and cleaved caspase-9 content in piglets with IUGR. In summary, FA supplementation could elevate antioxidant capacity and facilitate intestinal development, thus resulting in increased feed efficiency in piglets with IUGR.

Intrauterine growth retardation (IUGR) impairs postnatal growth and development in neonatal piglets. Ferulic acid (FA) is a ubiquitous phenolic compound that is present in numerous fruits and vegetables and possesses various biological activities. However, little is known about whether FA supplementation has beneficial effects on the growth performance, antioxidant capacity, and intestinal development of piglets with IUGR. Our findings provide important implications for treating piglets with IUGR after birth by stimulating intestinal development with FA supplementation.

Effect of Maternal Docosahexaenoic Acid Supplementation on Very Preterm Infant Growth: Secondary Outcome of a Randomized Clinical Trial.

INTRODUCTION: The aim of the study was to determine the effect of a maternal docosahexaenoic acid (DHA) supplementation during lactation, compared with a placebo, on the neonatal growth profile of breastfed very preterm infants. METHODS: Preterm infants' growth profile, growth velocity from birth to 36 weeks' postmenstrual age (PMA), and growth at 36 weeks' PMA were pre-specified secondary outcomes of a randomized placebo-controlled trial conducted in 16 Canadian neonatal intensive care units (2015-2018). Lactating mothers who delivered before 29 weeks' gestation were given 1.2 g of DHA daily or a placebo within 72 h of delivery and up to 36 weeks' PMA. Analyses were performed using a linear regression model with generalized estimating equations. RESULTS: 461 mothers and their 528 infants (DHA, N = 273; placebo, N = 255) were included with mean gestational age of 26.5 weeks (standard deviation [SD] = 1.6); 275 (52.1%) were males; mean birth weight was 895 g (SD = 240). DHA interaction with sex was significant on weight profile (interaction p < 0.001), weight velocity (interaction p = 0.05), and weight at 36 weeks' PMA (interaction p = 0.02). Females in the DHA group gained more weight compared to the placebo group (mean difference [MD], 52.6 g [95% confidence interval [CI]: 24.5-80.8], p < 0.001). Weight velocity was significantly higher in females of the DHA group (MD, 3.4 g/kg/day [95% CI: 0.6-6.2], p = 0.02). At 36 weeks' PMA, the weight of males in the DHA group was significantly smaller (MD, -88.9 g [95% CI: -166.2 to -11.6], p = 0.02). CONCLUSION: DHA positively affected female infants' neonatal weight profile and velocity and negatively affected male infants' weight at 36 weeks' PMA.

Taurine supplementation improves hippocampal metabolism in immature rats with intrauterine growth restriction (IUGR) through protecting neurons and reducing gliosis.

Taurine as an essential amino acid in the brain could play an important role in protecting the fetal brain of intrauterine growth restriction (IUGR). The hippocampus with IUGR showed neural metabolic disorder and structure changed that affected memory and learning ability. This study was aimed to identify the effect of taurine supplementation on the metabolism alterations and cellular composition changes of the hippocampus in IUGR immature rats. Metabolite concentrations were determined by magnetic resonance spectroscopy (MRS) in the hippocampus of juvenile rats with IUGR following taurine supplementation with antenatal or postnatal supply. The composition of neural cells in the hippocampus was observed by immunohistochemical staining (IHC) and western blotting (WB). Antenatal taurine supplementation increased the ratios of N-acetylaspartate (NAA) /creatine (Cr) and glutamate (Glu) /Cr of the hippocampus in the IUGR immature rats, but reduced the ratios of choline (Cho) /Cr and myoinositol (mI) /Cr. At the same time, the protein expression of NeuN in the IUGR rats was increased through intrauterine taurine supplementation, and the GFAP expression was reduced. Especially the effect of antenatal taurine was better than postpartum. Furthermore, there existed a positive correlation between the NAA/Cr ratio and the NeuN protein expression (R = 0.496 p < 0.001 IHC; R = 0.568 p < 0.001 WB), the same results existed in the relationship between the mI/Cr ratio and the GFAP protein expression (R = 0.338 p = 0.019 IHC; R = 0.440 p = 0.002 WB). Prenatal taurine supplementation can better improve hippocampal neuronal metabolism by increasing NAA / Cr ratio related to the number of neurons and reducing Cho / Cr ratio related to the number of glial cells.

Nano-selenium and Macleaya cordata Extracts Improved Immune Function and Reduced Oxidative Damage of Sows and IUGR Piglets After Heat Stress of Sows in Late Gestation.

To investigate the effects of nano-selenium (nano-Se) and Macleaya cordata extracts (MCE) on immune function and oxidative damage of sows and intrauterine growth retardation (IUGR) piglets exposed to heat stress (HS) in large-scale farms, a 2 × 2 factorial design was adopted in this test, and the two factors were nano-Se (0, 0.50 mg/kg) and MCE (0, 500 mg/kg). A total of 80 sows ([Landrace × Yorkshire] × Duroc, parity 2) were used in a 25-day trial from day 90 of gestation to delivery with 20 replications per group and 1 sow per replication. The dietary treatments of sows were as follows: (1) CON group, basic diet (0.30 mg/kg added Se, sodium selenite); (2) Nano-Se group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se; (3) MCE group, basic diet (0.00 mg/kg added Se) + 500 mg/kg added MCE; and (4) Combined group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se and 500 mg/kg added MCE. The activities of serum SOD, CAT, and GSH-Px of sows and IUGR piglets were significantly increased in MCE group and combined group, and the MDA content was extremely decreased. There were extreme differences in serum IgG level of sows and IUGR piglets, colostrum, and serum IgM level of IUGR piglets in MCE group and combined group compared with CON group. Maternal combined diets increased greatly the levels of serum IL-10 and IFN-γ of sows and IUGR piglets, and decreased extremely the contents of serum IL-1ß and TNF-α. MCE alone or combination with nano-Se in sow diets decreased greatly mRNA level of Hsp70 and increased mRNA level of Hsp27 in sows and IUGR piglets. In conclusion, nano-Se and/or MCE can be added to sow diets for the amelioration of HS-induced oxidative damage through improving immune function.

Strategies for intra-amniotic administration of fetal therapy in a rabbit model of intrauterine growth restriction.

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.

Maternal antioxidant treatment protects adult offspring against memory loss and hippocampal atrophy in a rodent model of developmental hypoxia.

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy.

Antenatal antioxidants to avert autism?

Paternally derived de novo mutations (DNMs) caused by oxidative stress (OS) have been implicated in the development of autism spectrum disorders (ASDs). Whether preconception antioxidant supplementation can reduce the incidence of ASDs by reducing OS is an area of uncertainty and potentially important future scientific investigation.

Male preconception antioxidant supplementation may lower autism risk: a call for studies.

Current research indicates that a sizable number of autism spectrum disorder (ASD) cases arise from de novo mutations (DNMs) occurring within the paternal germline, usually in an age-dependent manner. Andrologists have reported that somatic cells and gametes share the same pathologies that generate these DNMs-specifically, DNA hypomethylation caused by oxidative nucleoside base damage. Because many ASD researchers seek to identify genetic risk factors, teams are developing methods of assessing aberrant DNA patterns, such as parental gonadal mosaicism. Several studies propose antioxidant supplementation as a strategy to lower autism risk, and/or suggest connections between childhood neurodevelopmental disorders such as autism and paternally-derived DNMs. Actual data, however, are currently not available to determine whether male preconception antioxidant supplementation effectively lowers autism risk. The purpose of this paper is to (1) explore the mechanisms causing DNMs, specifically DNA hypomethylation; (2) explain how antioxidant supplementation may lower the risk of having a child with ASD; and, (3) advocate for the implementation of large prospective studies testing (2). These studies may very well find that male preconception supplementation with antioxidants prevents neurodevelopmental disorders in offspring, in much the same way that female prenatal consumption of folate was found to decrease the risk of birth defects. If this is indeed the case, the alarming rise in autism prevalence rates of the past few decades will slow-or even cease-upon the initiation of public awareness campaigns.

A pilot study on investigating the role of Salvia miltiorrhiza in fetal growth restriction.

To date there is no effective treatment for pregnancies complicated by fetal growth restriction (FGR). Salvia miltiorrhiza, a traditional Chinese herb has been shown to promote blood flow and improve microcirculatory disturbance. In this pilot study, we evaluated whether S. miltiorrhiza can potentially become a possible therapy for FGR. Nineteen pregnant women with FGR were treated with S. miltiorrhiza and ATP supplementation for an average of 7 days, and 17 cases received ATP supplementation as controls. The estimated fetal weights (EFWs) were measured by ultrasound after treatment, and the birthweights were recorded after birth. After treatment with S. miltiorrhiza, 7 (37%) FGR cases showed an increase in EFW to above the 10th percentile, compared with 4 (23%) FGR cases in controls (odds ratio: 1.896, 95% confidence limits (CLs): 0.44-8.144). At delivery, 10 (53%) FGR cases in the treatment group delivered babies with a birthweight above the 10th percentile, compared with 6 (35%) FGR cases in the control group (odds ratio: 2.037, 95% CL: 0.532-7.793); 80 or 64% FGR cases in the treatment group showed an increase in fetal abdominal circumference (AC) or biparietal diameter (BPD) above the 10th percentile before delivery. While 44 or 30% FGR cases in the control group showed an increase in AC or BPD. No improvement of head circumference (HC) or femur length (FL) was seen. These pilot data suggest the need for multicenter randomized clinical trials on the potential of S. miltiorrhiza to improve perinatal outcome in pregnant women complicated by FGR.

Dietary Supplementation of L-Arginine and N-Carbamylglutamate Attenuated the Hepatic Inflammatory Response and Apoptosis in Suckling Lambs with Intrauterine Growth Retardation.

L-arginine (Arg) is a semiessential amino acid with several physiological functions. N-Carbamylglutamate (NCG) can promote the synthesis of endogenous Arg in mammals. However, the roles of Arg or NCG on hepatic inflammation and apoptosis in suckling lambs suffering from intrauterine growth restriction (IUGR) are still unclear. The current work is aimed at examining the effects of dietary Arg and NCG on inflammatory and hepatocyte apoptosis in IUGR suckling lambs. On day 7 after birth, 48 newborn Hu lambs were selected from a cohort of 432 twin lambs. Normal-birthweight and IUGR Hu lambs were allocated randomly (n = 12/group) to control (CON), IUGR, IUGR+1% Arg, or IUGR+0.1% NCG groups. Lambs were fed for 21 days from 7 to 28 days old. Compared with CON lambs, relative protein 53 (P53), apoptosis antigen 1 (Fas), Bcl-2-associated X protein (Bax), caspase-3, cytochrome C, tumor necrosis factor alpha (TNF-α), nuclear factor kappa-B (NF-κB) p65, and NF-κB pp65 protein levels were higher (P < 0.05) in liver from IUGR lambs, whereas those in liver from IUGR lambs under Arg or NCG treatment were lower than those in IUGR lambs. These findings indicated that supplementing Arg or NCG reduced the contents of proinflammatory cytokines at the same time when the apoptosis-related pathway was being suppressed, thus suppressing the IUGR-induced apoptosis of hepatic cells.

Maternal curcumin supplementation ameliorates placental function and fetal growth in mice with intrauterine growth retardation†.

Intrauterine growth retardation (IUGR) is a serious reproductive problem in humans. The objective of this study was to investigate the effects of daily maternal curcumin supplementation during pregnancy on placental function and fetal growth in a mouse model of IUGR fed the low-protein (LP) diet. Pregnant mice were divided into four groups: (1) normal protein (19% protein) diet (NP); (2) LP (8% protein) diet; (3) LP diet + 100 mg/kg curcumin (LPL); (4) LP diet +400 mg/kg curcumin (LPH). The results showed that the LP group decreased fetal weight, placental weight, placental efficiency, serum progesterone level, placental glutathione peroxidase activity activity, blood sinusoids area, and antioxidant gene expression of placenta. In addition, in comparison with the NP group, LP diet increased serum corticosterone level, placental malondialdehyde content, and apoptotic index. Daily curcumin administration decreased the placental apoptosis, while it increased placental efficiency, placental redox balance, blood sinusoids area, and antioxidant-related protein expression in fetal liver. The antioxidant gene expression of placenta and fetal liver was normalized to the NP level after curcumin administration. In conclusion, daily curcumin supplementation could improve maternal placental function and fetal growth in mice with IUGR.

Addition of sildenafil citrate for treatment of severe intrauterine growth restriction: a double blind randomized placebo controlled trial.

Background: Severe intrauterine growth restriction complicates approximately 0.4% of the pregnancies. It increases the risk of perinatal morbidity and mortality.Subjects and methods: A double blind placebo controlled trial was conducted in Beni Suef University hospitals during 2017. It included 46 pregnant women with severe intrauterine growth restriction. Women were randomly allocated into two groups each included 23 patients. Intervention group received sildenafil citrate 20 mg orally three times a day, in addition to fish oil and zinc supplementation. Control group received tablets similar to sildenafil and the same treatment as intervention group. Primary outcomes included improvement in umbilical and middle cerebral arteries pulsatility indices and abdominal circumference.Results: Umbilical and middle cerebral arteries Doppler indices showed significant difference between groups after intake of sildenafil. Umbilical artery pulsatility index decreased significantly (p value = .001) while middle cerebral artery pulsatility index increased significantly in intervention group (p value0.001). Moreover, abdominal circumference growth velocity improved after two weeks of sildenafil intake (p value = .001).Conclusions: Sildenafil citrate may improve uteroplacental and fetal cerebral perfusion in pregnancies complicated by severe intrauterine growth restriction. It also improves abdominal circumference growth velocity. A wide scale randomized trials are needed for evaluation of neonatal and long term morbidity and mortality outcomes of pregnancies treated by sildenafil citrate.